This invention relates to new macrolide antibiotics with improved activity and methods of making them, the use of such antibiotics for the treatment of infectious diseases and compositions containing such macrolides.
The interest in macrolide antibiotics is increasing because these compounds are a very effective and safe class of agents against gram positive pathogens. Extensive spread of erythromycin A resistance among gram positive cocci isolates raised the urgent need for novel derivatives with improved activity, stability and antimicrobial spectra. The two most successful second generation agents derived from erythromycin A (Compound 1) through semisynthesis were its 6-O-methyl derivative clarithromycin (Compound 2) and the 15-membered azalide azithromycin (Compound 3) arising from a Beckman rearrangement. However, while featuring improved pharmacokinetics, none of these agents possessed a significant activity against bacterial isolates showing macrolide-lincosamide-streptogramine B (MLS B) cross resistance. 
Many different semisynthetic third generation derivatives of the ketolide class of macrolide antibiotics have been described, the most potent being HMR 3647 or telithromycin (Compound 4) (EP 680967 Al (1995); FR 2732684 Al (1996); Bioorg. Med. Chem. Lett. (1999), 9(21), 3075–3080.) and ABT 773 (WO 9809978 (1998); J. Med. Chem. 2000, 43, 1045). However, none of these agents described thus far have been able to overcome constitutive MLS B resistance in Staphylococcus aureus. 